Publications by authors named "Sean P Marrelli"

Alzheimer's disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured.

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Brain arteriovenous malformations (bAVMs) are direct connections between arteries and veins that remodel into a complex nidus susceptible to rupture and hemorrhage. Most sporadic bAVMs feature somatic activating mutations within KRAS, and endothelial-specific expression of the constitutively active variant KRASG12D models sporadic bAVM in mice. By leveraging 3D-based micro-CT imaging, we demonstrate that KRASG12D-driven bAVMs arise in stereotypical anatomical locations within the murine brain, which coincide with high endogenous Kras expression.

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  • Neutrophils play a harmful role after subarachnoid hemorrhage (SAH) by contributing to delayed cerebral ischemia (DCI) through the formation of neutrophil extracellular traps (NETs).
  • In a study using mice with induced SAH, therapies targeting neutrophils, such as depletion and PAD4 inhibition, significantly improved cerebral blood flow and neurological outcomes by reducing the formation of NETs.
  • Human patients with SAH who experienced DCI had higher levels of NET markers in their blood, indicating that targeting neutrophils and NETosis could be a potential therapeutic strategy.
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pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusion of the distal internal carotid arteries. A smooth muscle cell (SMC)-specific knock-in mouse model () inserted the mutation into 67% of aortic SMCs, whereas explanted SMCs were uniformly heterozygous. SMCs fail to fully differentiate and maintain stem cell-like features, including high glycolytic flux, and increasing oxidative respiration (OXPHOS) with nicotinamide riboside (NR) drives the mutant SMCs to differentiate and decreases migration.

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Introduction: Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery.

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  • The study focuses on the role of G-quadruplex (G4) DNA structures, formed by noncanonical base pairing among guanines, and their impact on gene expression in neurons.
  • Researchers used a ligand called pyridostatin (PDS) to stabilize G4 structures, which led to the discovery of 901 differentially expressed genes in neurons, affecting crucial processes like p53 signaling and memory functions.
  • The findings highlight a new mechanism involving the E3 ubiquitin ligase Pirh2, which is linked to DNA damage responses and increased G4-DNA levels, suggesting that G4 stabilization may influence both gene regulation and DNA integrity in neurons.
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Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair.

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Laser speckle contrast imaging (LSCI) offers the ability to measure relative cerebral blood flow (CBF) through the intact skull in mice. LSCI can be used to measure changes in cortical CBF in the middle cerebral artery occlusion/reperfusion (MCAo/R) stroke model. However, because conventional LSCI approaches are designed to image from above, uninterrupted measurement of CBF during the MCAo/R procedure is not possible due to the need to repeatedly reposition the mouse between prone and supine positions.

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Microglia, the resident innate immune cells of the brain, become more highly reactive with aging and diseased conditions. In collaboration with other cell types in brains, microglia can contribute both to worsened outcome following stroke or other neurodegenerative diseases and to the recovery process by changing their phenotype toward reparative microglia. Recently, IFITM3 (a member of the "interferon-inducible transmembrane" family) has been revealed as a molecular mediator between amyloid pathology and neuroinflammation.

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  • Research into the gut microbiome and its metabolites, particularly trimethylamine N-oxide (TMAO), has gained significant attention in the last 30 years due to their effects on health.
  • TMAO, produced from dietary sources like choline and carnitine, plays a role in brain functions such as development, neurogenesis, and behavior, as it can cross the blood-brain barrier.
  • Altered levels of TMAO are linked to various health issues, including metabolic and neurodegenerative disorders, by influencing oxidative stress and neuroinflammation, which can lead to psychiatric and cognitive problems.
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Post-menopausal women become vulnerable to stroke and have poorer outcomes and higher mortality than age-matched men, and previous studies suggested that sex chromosomes play a vital role in mediating stroke sensitivity in the aged. It is unknown if this is due to effects of the X or Y chromosome. The present study used the XY* mouse model (with four genotypes: XX and XO gonadal females and XY and XXY gonadal males) to compare the effect of the X vs.

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Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts.

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Background: CD146 is a tight junction-associated molecule involved in maintaining endothelial barrier, and balancing immune-inflammation response, in cardiovascular disease. Notably, peripheral CD146 cells significantly upsurge under vessel dyshomeostasis such as acute myocardial injury (AMI), appearing to be a promising therapeutic target. In this study, with a new view of gene correlation, we aim at deciphering the complex underlying mechanism of CD146 cells' impact in the development of AMI.

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  • Secondary injury after a cortical stroke leads to delayed gliosis and neuronal loss in the thalamus, with the effects varying by age.
  • In young and aged mice, gliosis increased significantly over time post-stroke, with aged mice showing less microgliosis and astrogliosis compared to the young.
  • Treatment with memantine, an NMDA receptor antagonist, within 24 hours of the stroke notably reduced gliosis, highlighting its potential to mitigate secondary injury in the thalamus.
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Background: Brain temperature is a strong determinant of ischemic stroke injury. For this reason, tight management of brain or body temperature (Tcore) in experimental rodent stroke models is recommended to improve the rigor and reproducibility of outcomes. However, methods for managing Tcore during and after stroke vary widely in approach and effectiveness.

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Background And Purpose: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline.

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It is well-established that the kidney collecting duct (CD) plays a central role in regulation of systemic water homeostasis. Aquaporin 2 (AQP2)-dependent water reabsorption in the CD critically depends on the arginine vasopressin (AVP) antidiuretic input and the presence of a favorable osmotic gradient at the apical plasma membrane with tubular lumen being hypotonic compared to the cytosol. This osmotic difference creates a mechanical force leading to an increase in [Ca2+]i in CD cells.

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Recent advances in three-dimensional (3D) fluorescence microscopy offer the ability to image the entire vascular network in entire organs, or even whole animals. However, these imaging modalities rely on either endogenous fluorescent reporters or involved immunohistochemistry protocols, as well as optical clearing of the tissue and refractive index matching. Conversely, X-ray-based 3D imaging modalities, such as micro CT, can image non-transparent samples, at high resolution, without requiring complicated or expensive immunolabeling and clearing protocols, or fluorescent reporters.

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Neonatal hypoxia-ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways.

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Background and Purpose- VWF (von Willebrand factor) strings mediate spontaneous platelet adhesion in the vascular lumen, which may lead to microthrombi formation and contribute to stroke pathology. However, the mechanism of VWF string attachment at the endothelial surface is unknown. We tested the novel hypothesis that VWF strings are tethered to the endothelial surface through an interaction between extracellular vimentin and the A2 domain of VWF.

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Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS).

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Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis, but the effects of exercise on ER stress-mediated endothelial dysfunction in atherosclerosis is not yet fully understood. We assessed endothelium-dependent vasodilation in isolated mesenteric arteries from wild type (WT), WT with exercise (WT-EX), ApoE knockout (ApoE KO), and ApoE KO mice with exercise (ApoE KO-EX). Vasodilation to acetylcholine (ACh) was elicited in the presence of inhibitors of ER stress, eNOS, caspase-1, and UCP-2 (Tudca, L-NAME, AC-YVARD-cmk, and Genipin, respectively) and the ER stress inducer (Tunicamycin).

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